Epilepsy is one of the most common neurological disorders in humans. The etiology of epilepsy is complex, with the contribution of both environmental and genetic factors. Linkage analysis and candidate gene studies have enabled the discovery of several epilepsy genes, mutations in which cause rare, autosomal dominant or sporadic forms of epilepsy. Despite these advances, for the vast majority of individuals with epilepsy, the genetic cause is unknown. Recent advances in technology now permit genome-wide analyses for both copy number and sequence changes. Unlike genome-wide studies in many neurodevelopmental disorders, there are no published genome-wide studies in epilepsy to date. The overall goal of this study is to use genomic approaches, including array comparative genomic hybridization and whole exome sequencing, to identify novel candidate genes for epilepsy. We will perform genome-wide array CGH analysis for copy number changes in a cohort of 2000 individuals with epilepsy. We will also use next- generation sequencing technology to perform exome sequencing to identify mutations in a subset of individuals with severe childhood-onset encephalopathy. Each of these whole-genome technologies offers an unbiased approach for identifying novel candidate genes and pathways for epilepsy. We will then use the results of these studies to inform selection of candidate genes for resequencing in 500 affected individuals. The discovery of novel genes and pathways in epilepsy using the genomic approaches within this proposal will further our understanding of brain development and epileptogenesis and allow better prognosis and recurrence risk counseling for families.